St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole

OBJECTIVE: St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. METHODS: Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or a 300-mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection. RESULTS: Omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent pharmacokinetic profiles. After a 14-day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (C(max)) significantly decreased by 37.5% +/- 13.3% (P =.001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% +/- 20.7% (P =.017) in CYP2C19*1/CYP2C19*1; the area under the concentration-time curve extrapolated to infinity [AUC(0- infinity )] decreased by 37.9% +/- 21.3% (P =.014) and 43.9% +/- 23.7% (P =.011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the C(max) and AUC(0- infinity ) of omeprazole sulfone increased by 160.3% +/- 45.5% (P =.001) and by 136.6% +/- 84.6% (P =.014), 155.5% +/- 58.8% (P =.001), and 158.7% +/- 101.4% (P =.017) in mutant and wild genotypes, respectively. St John's wort increased the C(max) of 5-hydroxyomeprazole by 38.1% +/- 30.5% (P =.028) and the AUC(0- infinity ) by 37.2% +/- 26% (P =.005) in CYP2C19 wild-type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes. CONCLUSION: St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.     

The interaction between St John's wort and an oral contraceptive

OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Twelve healthy premenopausal women who were using oral contraception (>3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. RESULTS: Concomitant use of St John's wort was associated with a significant (P <.05) increase in the oral clearance of norethindrone (8.2 +/- 2.7 L/h to 9.5 +/- 3.4 L/h, P =.042) and a significant reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023). The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3 L/h, P =.007) during St John's wort administration, but the systemic clearance of midazolam was unchanged (37.7 +/- 11.3 L/h to 39.0 +/- 10.3 L/h, P =.567). Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St John's wort dosing (P >.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005). CONCLUSION: St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort.     

Effect of St John's wort on imatinib mesylate pharmacokinetics

OBJECTIVE: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity.Thus we examined the effects of St John's wort on imatinib pharmacokinetics. METHODS: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. RESULTS: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered. CONCLUSIONS: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.     

The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity.

BACKGROUND: St John's wort (Hypericum perforatum) is a popular over-the-counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) isozymes. The effect of St John's wort on CYP activity in vivo was examined with a probe drug cocktail. METHODS: Twelve healthy subjects (5 female, 7 male) completed this 3-period, open-label, fixed schedule study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6), oral midazolam (intestinal wall and hepatic CYP3A), and intravenous midazolam (hepatic CYP3A) were administered before, with short-term St John's wort dosing (900 mg), and after 2 weeks of intake (300 mg 3 times a day) to determine CYP activities. RESULTS: Short-term administration of St John's wort had no effect on CYP activities. Long-term St John's wort administration caused a significant (P <.05) increase in oral clearance of midazolam from 121.8 +/- 70.7 to 254.5 +/- 127.8 and a corresponding significant decline in oral bioavailability from 0.28 +/- 0.15 to 0.17 +/- 0.06. In contrast to the >50% decrease in the area under the plasma concentration-time curve (AUC) when midazolam was administered orally, long-term St John's wort administration caused a 20% decrease in AUC when midazolam was given intravenously. There was no change in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St John's wort administration. CONCLUSION: Long-term St John's wort administration resulted in a significant and selective induction of CYP3A activity in the intestinal wall. St John's wort did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. Reduced therapeutic efficacy of drugs metabolized by CYP3A should be anticipated during long-term administration of St John's wort.     

Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism

OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin-angiotensin system act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET-1), norepinephrine (NA), and angiotensin II (ANGII). METHODS: Thirty-seven individuals were included in a randomized, double-blind, placebo-controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET-1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n=18) and skin microcirculation (n=12), respectively. RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96). Venoconstriction to ET-1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET-1 and NA (median effective concentration [ED50] for ET-1 after darusentan [placebo]: 2.5 +/- 0.2 pmol/min for CT/TT [2.7 +/- 0.3 pmol/min], P=.42; 3.9 +/- 0.6 pmol/min for CC [4.6 +/- 0.3 pmol/min], P=.42; P=.046 [P=.0005] for CT/TT versus CC) (ED50 for NA after darusentan [placebo]: 5.2 +/- 1.2 ng/min for CT/TT [7.3 +/- 1.2 ng/min], P=.20; 32.9 +/- 7.1 ng/min for CC [19.7 +/- 5.5 ng/min], P=.75; P=.0008 [P=.026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 +/- 0.05 mm, P=.004 versus placebo). Systemic ET A antagonism inhibited constriction to ET-1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET-1, P=.017 for all individuals versus placebo; NA, P=.0005; and ANGII, P=.002). CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET-1 and NA. Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET-1-mediated or NA-mediated venoconstriction, indicating that, in the presence of high local ET-1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far.     

Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum).

OBJECTIVE: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin. METHODS: The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). RESULTS: There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. CONCLUSION: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter.     

Human pharmacology of the methamphetamine stereoisomers

OBJECTIVE: To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers. METHODS: In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for "intoxication," "good drug effect," and "drug liking") were obtained. RESULTS: Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3-15.0 hours) than for d-methamphetamine (10.2-10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 +/- 23.4 beats/min, 13.5 +/- 18.5 beats/min, and 10.7 +/- 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 +/- 17.8 beats/min and 34.5 +/- 18.9 beats/min, respectively, versus 19.5 +/- 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 +/- 35.3 versus 30.3 +/- 24.9) and drug liking (47.7 +/- 35.1 versus 28.6 +/- 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures. CONCLUSION: The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities.     

St. John's wort has no effect on pain in polyneuropathy

Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy but cannot be used in a substantial number of patients. St. John's wort is a herbal antidepressant, which may act via mechanisms similar to the tricyclics. The aim of this study was to test if St. John's wort would relieve painful polyneuropathy. The study design was randomized, double-blind, placebo-controlled and cross-over. Fifty-four patients were assigned to one of the two treatment sequences. The daily dose of St. John's wort was three tablets each containing 900 microg totalhypericin. During the two treatment periods of 5 weeks duration, patients rated constant pain, lancinating pain paroxysms, touch-evoked pain and pain on pressure by use of 0--10 point numeric rating scales. Forty-seven patients -- 18 diabetics and 29 non-diabetics -- completed the study. There was a trend of lower total pain score (sum of the individual pain scores) on St. John's wort than on placebo (median 14 vs. 15, P=0.05). None of the individual pain ratings were significantly changed by St. John's wort as compared to placebo (P=0.09--0.33). Complete, good or moderate pain relief was experienced by nine patients with St. John's wort and two with placebo (P=0.07). In conclusion, St. John's wort has no significant effect on pain in polyneuropathy.     

Effect of St John's wort on the pharmacokinetics of fexofenadine

BACKGROUND: St John's wort is a popular over-the-counter dietary supplement and herbal remedy that has been implicated in drug interactions with several substrates of P-glycoprotein. The effect of St John's wort on P-glycoprotein activity in vivo was examined with use of fexofenadine as selective probe drug. METHODS: A 3-period, open-label, fixed-schedule study design was used. Fexofenadine, 60 mg, was administered orally before administration of St John's wort, with a single dose of St John's wort (900 mg), and after 2 weeks of treatment with St John's wort (300 mg 3 times a day) to determine P-glycoprotein activity. RESULTS: A single dose of St John's wort significantly (P <.05) increased the maximum plasma concentration of fexofenadine by 45% and significantly (P <.05) decreased the oral clearance by 20%, with no change in half-life or renal clearance. Long-term administration of St John's wort did not cause a significant change in fexofenadine disposition relative to the untreated phase. Compared with the single-dose treatment phase, long-term St John's wort caused a significant 35% decrease (P <.05) in maximum plasma concentration and a significant 47% increase (P <.05) in fexofenadine oral clearance. CONCLUSIONS: A single dose of St John's wort resulted in a significant inhibition of intestinal P-glycoprotein. Long-term treatment with St John's wort reversed the changes in fexofenadine disposition observed with single-dose administration.     

The effects of cardioselective and non-selective beta-adrenoceptor blockade on the hypokalaemic and cardiovascular responses to adrenomedullary hormones in man

Adrenaline was infused intravenously in nine normal volunteers to plasma concentrations similar to those found after myocardial infarction. This study was undertaken on three occasions after 5 days' treatment with placebo or the beta-adrenoceptor antagonists, atenolol or timolol. Adrenaline increased the systolic pressure by 11 mmHg, decreased the diastolic pressure by 14 mmHg, and increased the heart rate by 7 beats/min. These changes were prevented by atenolol. However, after timolol the diastolic pressure rose (+19 mmHg) and heart rate fell (-8 beats/min). Adrenaline caused the corrected QT interval (QTc) to lengthen (0.36 +/- 0.02 s to 0.41 +/- 0.06 s). No significant changes were found in the QTc when subjects were pretreated with atenolol or timolol. The serum potassium fell from 4.06 to 3.22 mmol/l after adrenaline. Serum potassium fell to a lesser extent to 3.67 mmol/l after atenolol and actually increased to 4.25 mmol/l after timolol. Adrenaline-mediated hypokalaemia appears to result from the stimulation of a beta 2-adrenoceptor linked to membrane Na+/K+-ATPase causing potassium influx.     

Cardiac function during mental stress: cholinergic modulation with pyridostigmine in healthy subjects

Mentally or emotionally stressful situations occur throughout our lives and cause physiological haemodynamic responses. In patients with coronary artery disease, such events can also induce myocardial ischaemia and ventricular arrhythmias, increasing mortality rates. The purpose of the present study was to determine the acute effects of the oral administration of pyridostigmine, a reversible cholinesterase inhibitor and thus an indirect cholinomimetic drug, on echocardiographic variables during mental stress in healthy subjects. A total of 18 healthy young volunteers were subjected to mental stress tests (mental arithmetic and the Stroop colour-word test) 2 h after the oral administration of either placebo or pyridostigmine bromide (45 mg), using a balanced-randomized, double-blind, crossover protocol. During mental stress, heart rate (pyridostigmine, 64+/-1 beats/min; placebo, 70+/-1 beats/min; P =0.0003) and diastolic blood pressure (pyridostigmine, 66+/-2 mmHg; placebo, 79+/-3 mmHg; P =0.01) were lower in the pyridostigmine group, but systolic pressure was not (pyridostigmine, 124+/-3 mmHg; placebo, 123+/-3 mmHg; P =0.40). There were no detectable abnormalities in the left ventricular wall motion score during mental stress, but left ventricular outflow tract mean velocity (pyridostigmine, 0.68+/-0.02 m/s; placebo, 0.64+/-0.02 m/s; P <0.05) and mitral inflow velocity deceleration (placebo, 4.05+/-0.18 m/s(2); pyridostigmine, 4.41+/-0.16 m/s(2); P <0.05) were higher in the pyridostigmine group. In conclusion, cholinergic stimulation with pyridostigmine seems to increase left ventricular diastolic function during mental stress in healthy subjects.     

St. John's wort

St. John's wort has been used to treat a variety of conditions. Several brands are standardized for content of hypericin and hyperforin, which are among the most researched active components of St. John's wort. St. John's wort has been found to be superior to placebo and equivalent to standard antidepressants for the treatment of mild to moderate depression. Studies of St. John's wort for the treatment of major depression have had conflicting results. St. John's wort is generally well tolerated, although it may potentially reduce the effectiveness of several pharmaceutical drugs.     

Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

SKF 82526-J, or fenoldopam, a benzazepine derivative, is a selective dopamine-1 (DA-1) agonist devoid of activity at dopamine-2, alpha- or beta-adrenergic receptors. We studied SKF 82526-J in 10 patients with essential hypertension and five normal control subjects on constant 150-meq sodium, 60 meq potassium intake. In the hypertensive patients, during a 6-d placebo period supine blood pressure and heart rate were stable at 156 +/- 6/105 +/- 4 mmHg and 76 +/- 5 beats/min, respectively. In response to a single oral dose of 100 mg of SKF 82526-J, supine blood pressure decreased to a nadir of 141 +/- 5/89 +/- 8 mmHg (P less than 0.0001) at 90 min and remained decreased at 145 +/- 6/99 +/- 3 mmHg (P less than 0.0001) at 4 h. Heart rate increased to 91 +/- 5 beats/min (P less than 0.002), but returned to control levels (82 +/- 5 beats/min) at 4 h. Renal blood flow increased from 371 +/- 57 to a peak of 659 +/- 104 ml/min and renal vascular resistance fell from 34 +/- 5 to 19 +/- 2 dyn sec cm-5 X 10(3) (P less than 0.01). Urine volume, sodium and fractional sodium excretion, and plasma renin activity were increased as a result of SKF 82526-J administration. During the ensuing 3 wk of SKF 82526-J, blood pressure remained decreased and returned to control levels after placebo administration. In contrast, in normal subjects SKF 82526-J administration was associated with a small transient reduction in diastolic pressure only. These results suggest that reduced dopaminergic activity expressed at the peripheral DA-1 receptor may contribute to the pathophysiology and/or maintenance of increased blood pressure in essential hypertension. In addition, the results suggest that peripheral DA-1 receptor stimulation with SKF 82526-J may be efficacious in the treatment of human essential hypertension.     

St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism

OBJECTIVE: Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans. METHODS: Jejunal single-pass perfusion experiments with 120-mg/L (244 micromol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4-formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively. RESULTS: St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration-time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P <.0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P <.0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P <.01) and 63% (P <.0001), respectively. CONCLUSIONS: Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.     

Lack of effect of St John's Wort on carbamazepine pharmacokinetics in healthy volunteers

BACKGROUND: St John's Wort is a popular herbal product used by approximately 7% of patients with epilepsy. Previous reports have described reductions in concentrations of CYP3A4 substrates indinavir and cyclosporine (INN, ciclosporin) associated with St John's Wort. OBJECTIVE: Our objective was to determine the effect of St John's Wort on steady state carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics. METHODS AND SUBJECTS: Eight healthy volunteers (5 men; age range, 24-43 years) participated in this unblinded study. Subjects received 100 mg of carbamazepine twice daily for 3 days, 200 mg twice daily for 3 days, and then 400 mg once daily for 14 days. Blood samples were collected before and 1, 2, 4, 6, 8, 10, 12, and 24 hours after the dose on day 21. The subjects then took 300 mg of St John's Wort (0.3% hypericin standardized tablet) 3 times daily with meals and with carbamazepine for 14 days. On day 35, blood sampling was repeated. Plasma samples were analyzed for carbamazepine and carbamazepine-10,11-epoxide with HPLC. We compared carbamazepine and carbamazepine-10,11-epoxide noncompartmental pharmacokinetic parameter values before and after St John's Wort with a paired Student t test. RESULTS: We found no significant differences before or after the administration of St John's Wort in carbamazepine peak concentration (7.2 +/- 1 mg/L before versus 7.6 +/- 1.3 mg/L after), trough concentration (4.8 +/- 0.5 mg/L before versus 4.3 +/- 0.8 mg/L after), area under the plasma concentration-time curve (142.4 +/- 12.9 mg x h/L before versus 143.8 +/- 27.2 mg x h/L after), or oral clearance (2.8 +/- 0.3 L/h before versus 2.9 +/- 0.6 L/h after). Similarly, no differences were found in peak concentration (2 +/- 0.5 mg/L before versus 2.1 +/- 0.4 mg/L after), trough concentration (1.3 +/- 0.3 mg/L before versus 1.4 +/- 0.3 mg/L after), and area under the plasma concentration-time curve (37.5 +/- 7.4 mg x h/L before versus 41.9 +/- 10.3 mg x h/L after) of carbamazepine-10,11-epoxide. CONCLUSIONS: The results suggest that treatment with St John's Wort for 14 days did not further induce the clearance of carbamazepine.     

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.     

Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6+/-1.0 versus 7.2+/-1.2 mmHg; means+/-S.E.M., P<0.02), HR (59+/-2 versus 66+/-3 beats/min, P<0.05) and MSNA burst frequency (29.0+/-2.4 versus 39.0+/-3.5 bursts/min, P<0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2+/-0.6 versus 8.8+/-1.4 bursts/100 heart beats per mmHg; P<0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.     

Nicotine enhances the circulatory effects of adenosine in human beings

A randomized, double-blind, and placebo-controlled study was performed in 10 healthy volunteers to evaluate a possible interaction between adenosine and nicotine in human beings. The infusion of adenosine alone (0.07 mg/kg/min) induced an increase in heart rate of 4.7 beats/min versus 0.2 beats/min after placebo administration (p less than 0.02). The infusion of adenosine alone induced a decrease in finger skin temperature compared with placebo administration (-1.0 degrees versus 0.0 degrees C, p less than 0.01). When compared with baseline values, nicotine gum chewing increased systolic and diastolic blood pressures by 6.2 and 7.0 mm Hg, respectively (p less than 0.001), heart rate by 5.5 beats/min (p less than 0.01), and plasma adrenaline levels by 0.03 nmol/L (p less than 0.025), whereas skin temperatures fell by 1.3 degrees C (p less than 0.001). The nicotine-induced increase in heart rate was larger during adenosine infusion than during placebo administration (14.9 versus 5.5 beats/min, p less than 0.001), whereas the increment of diastolic blood pressure was lower (1.1 versus 4.0 mm Hg, p less than 0.05). The increment in systolic blood pressure was not altered by concomitant adenosine infusion. The rise in plasma noradrenaline levels during the combined administration of nicotine and adenosine differed significantly from the response to nicotine alone (+ 0.23 versus -0.05 nmol/L, p less than 0.02). We concluded that, in human beings, the characteristic hemodynamic response to adenosine infusion is enhanced by nicotine.     

Effect of intravenous infusion of adrenaline on the cardiovascular responses to distal body subatmospheric pressure in man

1. On two separate occasions, at least 1 week apart, seven young healthy male subjects received intravenous infusions of either adrenaline [0.27 nmol (50 ng) min-1 kg-1] or saline (154 mmol/l NaCl), plus ascorbic acid (5.68 mmol/l), over 30 min. 2. On each occasion, the subjects were exposed to distal body subatmospheric pressure (DBSP), 0 to 50 mmHg (0 to 6.65 kPa) in 10 mmHg (1.33 kPa) steps, before infusion, during the final 15 min of the infusion, and at 15 min and 30 min after the cessation of the infusion. 3. Venous adrenaline concentrations of 2.85 +/- 0.22 nmol/l were achieved during the adrenaline infusion, compared with 0.49 +/- 0.07 nmol/l during the saline infusion (P less than 0.001). At 15 min and at 30 min after cessation of the adrenaline infusion, venous adrenaline concentrations had fallen to levels similar to those achieved after the cessation of the saline infusion. 4. Heart rate rose significantly from 58 +/- 4 beats/min to 67 +/- 4 beats/min during the adrenaline infusion (P less than 0.05), but there was no further significant change in response to 50 mmHg (6.65 kPa) DBSP. At 30 min after the cessation of the adrenaline infusion, heart rate rose from 60 +/- 4 beats/min to 78 +/- 7 beats/min in response to 50 mmHg DBSP. This increase was significantly greater than that observed before the adrenaline infusion [58 +/- 4 beats/min to 69 +/- 7 beats/min during 50 mmHg (6.65 kPa) DBSP; P less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)